Giulio Superti-FurgaMolecular Networks and Systems Pharmacology

The Superti-Furga laboratory addresses the mechanisms by which cells respond to challenges that perturb homeostasis, may these challenges be drugs, viruses or oncogenic mutations, and how homeostasis can subsequently be restored. Strategically, the laboratory investigates large networks of proteins, genes and metabolites, while also focusing on the mechanistic understanding of individual proteins, protein complexes and drug function. How does a drug really work, what are its cellular binding partners or targets, what molecular effects does it cause? How does a virus perturb a cell without the cell noticing? And which are the cell’s weapons to thwart such an attack? Can one detect a perturbed and thus vulnerable “state” of cancer cells, particularly leukemia, by looking at the composition and regulation of the molecular machinery?

The research focus in the Superti-Furga laboratory is on challenging existing paradigms of drug, virus or oncogene action to obtain novel, more comprehensive views that take biological complexity into consideration in view of links to many genes and gene products, investigating metabolism and drug synergies. Efforts are focused on blood cancers, metabolism, infection and inflammation. The approach is truly interdisciplinary and involves functional genomics and proteomics, structural analysis, chemical biology, high-content imaging, bioinformatics and physiology, reflecting the blend of expertise of the laboratory members.

Molecular Networks

In an era of exploding genomic information, the Superti-Furga laboratory is specialized in translating genomic data into biological significance. The laboratory is characterizing the different biological functions of cells as the outcome of molecular networks of gene products such as proteins, protein complexes, RNAs and metabolites. Inevitably, a pathogenic status is manifested in alterations of these molecular networks. Entire biological pathways are mapped and linked with other cellular processes. We also characterize the basic functional units of cellular action, the multi-protein complexes forming molecular machines, in sufficient detail to identify potential medical exploitation. The disease focus is cancer (Chronic Myelogenous Leukemia, Mixed Lineage Leukemia, Acute Myeloid Leukemia, other cancers), infections, mostly viral, and inflammation.

Systems Pharmacology

Most drugs work not only by engaging a single target, but by producing large, complex perturbations of biological systems. The Superti-Furga laboratory has developed or adapted a variety of chemical biology approaches such as chemo-proteomics, genome editing and haploid genetic screens to understand drug action at the molecular level. The laboratory has also developed a small molecule interaction mapping technology using mass spectrometric thermal stability shifts at the proteome-wide level, allowing to investigate the impact of any molecule on intact cells on a global scale. Historically, the lab has identified new targets for known drugs, previously unknown mechanisms of drug resistance, “effector” genes for the compounds (genes required for the drug to exert its action), mechanisms of synergy between compounds and, in a few cases, new medical use of existing drugs. By investigating existing drugs with unclear mode of action on rapidly dividing cancer cells and using its arsenal of innovative technologies to uncover their molecular mechanism, the Superti-Furga laboratory has recently identified a new drug target in a poorly characterized pathway involved in the metabolism of oxidized nucleotides. In general, the expectation is that the systematic adoption of this more rigorous and “systems-level” characterization of chemical entities will help understanding the biology of drug action better and allow the development of improved drugs. It should help the community in rationalizing patient stratification, thus increasing the efficacy of clinical trials and reduce unwanted side effects, but also contribute to the employment of mechanism-based combination therapy with existing drugs.

Metabolism and membrane transporters

All cells are surrounded by a lipid bilayer representing a “greasy seal” between the aqueous inside of the cell and the outside. Yet the cells needs to import nutrients, water, ions to sustain their internal metabolism to produce energy and the building blocks required to safeguard and replicate the genetic material and the rest of the cellular infrastructure. The Superti-Furga laboratory has recently found that lipid membrane composition is regulated according to a “code” that links every individual lipid species and metabolism to specific cellular functions. While only a few molecules are thought to be able to pass through the fat membrane surrounding cells, the vast majority of molecules, including vitamins, small molecule hormones, xenobiotics, phytochemicals, pesticides, microbiome metabolites and, importantly, drugs require transporters to enter. The membrane transporters can be thus considered the managers of the interface between chemistry and biology and between organisms and their environment. The Superti-Furga laboratory has recently found transporters of the Solute Carriers group of proteins (SLCs) that are required for cancer drugs to enter cells and exert their activity and others that are required to couple nutrient availability to growth, in a novel signaling function. As they are overall a large and neglected gene family in humans, membrane transporters of the SLC group (and ABC) and their roles in metabolism, drug transport and signaling will be investigated heavily in the laboratory. A better understanding of the transport and signaling specificity of individual SLCs and their concerted circuits may on one hand lead to better targeted drugs and on the other hand pave the way for an understanding of how biological systems are integrated with their environment.

Biosketch

Giulio Superti-Furga, Italian. Studies in molecular biology at the University of Zurich, Genentech Inc. and IMP Vienna (Meinrad Busslinger). Post-doctoral fellow and Team Leader at EMBL Heidelberg (Giulio Draetta/Sara Courtneidge). Co-founder of the biotech companies Cellzome (scientific director) and Haplogen/Haplogen Genomics (SAB). Member of: Austrian Academy of Sciences, German Academy of Sciences, EMBO, European Academy of Cancer Sciences, Academia Europaea. Chair of the EMBL Alumni Association. 2009, Advanced Investigator ERC Grant recipient and Knight Officer Order of Merit of the Republic of Italy. 2011, Prize of the City of Vienna for Natural Sciences and “Austria´s Scientist of the Year”. Since 2005, Scientific Director of CeMM, located in the middle of the large general hospital campus in Vienna, where, together with some 140 scientists and medical doctors, he is pioneering the scientific and technical basis for precision medicine. Among his major achievements to date are the discovery of fundamental organization principles of the proteome of higher organisms, the elucidation of new pathways in cancer and innate immunity as well as the establishment of a world-unique experimental framework to decipher the molecular mechanism of action of drugs. His works on molecular networks of the entire yeast or of disease-relevant human pathways are among the most highly cited in the field.